Researchers have demonstrated modest progress towards the goal of making the body's existing cell populations rebuild damaged cartilage in situ:

A small molecule dubbed kartogenin encourages stem cells to take on the characteristics of cells that make cartilage, a new study shows. And treatment with kartogenin allowed many mice with arthritis-like cartilage damage in a knee to regain the ability to use the joint without pain. ... The new approach taps into mesenchymal stem cells, which naturally reside in cartilage and give rise to cells that make connective tissue. These include chondrocytes, the only cells in the body that manufacture cartilage.

...

"In the blue-sky scenario, this would be a locally delivered therapy that would target stem cells already there," says study coauthor Kristen Johnson, a molecular biologist at the Genomics Institute of the Novartis Research Foundation in San Diego. Johnson and her colleagues screened 22,000 compounds in cartilage and found that one, kartogenin, induced stem cells to take on the characteristics of chondrocytes. The molecule turned on genes that make cartilage components called aggrecan and collagen II. Tests of mice with cartilage damage similar to osteoarthritis showed that kartogenin injections lowered levels of a protein called cartilage oligomeric matrix protein. People with osteoarthritis have an excess of the protein, which is considered a marker of disease severity. Kartogenin also enabled mice with knee injuries to regain weight-bearing capacity on the joint within 42 days.

As a long term goal for tissue engineering, controlling existing cell populations sufficiently well to rebuild lost or damaged structures in the body is preferable to strategies that involve surgery - such as, for example, building cartilage outside the body and then implanting it. Both avenues are under development at this time.

One consequence of an increased focus on controlling stem cells in the body is that researchers must find ways to reverse the stem cell decline that comes with aging. If stem cell populations are generally less effective, then therapies based on directing those cells may be of limited benefit. Given that most of the regenerative therapies we can envisage will be of greatest use to the elderly, the people who bear the most damage and bodily dysfunction, and who are generally the wealthiest portion of the population, there is a strong financial incentive to find ways to build working therapies for that market. This is why I see the regenerative medicine community blending in at the edges with the longevity science community in the years to come - many of the goals are much the same.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An interesting experiment, especially when compared with work on brain aging that focuses on levels of cell proliferation: "During the past decade, it has become increasingly clear that consistent changes in the levels of expression of a small cohort of genes accompany the aging of mammalian tissues. In many cases, these changes have been shown to generate features that are characteristic of the senescent phenotype. Previously, a small pilot study indicated that some of these changes might be reversed in rat liver, if the liver cells became malignant and were proliferating. The present study has tested the hypothesis that inducing proliferation in old rat liver can reset the levels of expression of these age-related genes to that observed in young tissue. A microarray approach was used to identify genes that exhibited the greatest changes in their expression during aging. The levels of expression of these markers were then examined in transcriptomes of both proliferating hepatomas from old animals and old rat liver lobes that had regenerated after partial hepatectomy but were again quiescent. We have found evidence that over 20% of the aging-related genes had their levels of expression reset to young levels by stimulating proliferation, even in cells that had undergone a limited number of cell cycles and then become quiescent again. Moreover, our network analysis [may] provide insights into mechanisms involved in longevity and regeneration that are distinct from cancer."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22477361

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An example of work that lays the foundations for lung tissue engineering, which has been lagging behind advances for other organs: "How do you grow stem cells into lungs? The question has puzzled scientists for years. First you need the right recipe, and it took [researchers] seven years of trial and error and painstaking science to come up with it. ... Some tissues, like muscle and nerves, are relatively easy to grow, but others, including liver, lung, thyroid, and pancreas, have been much more difficult. These troublesome tissues all spring from the endoderm, the innermost layer of an early embryo. The endoderm forms when an embryo is about three weeks old and differentiates into organs as early as five weeks. Somehow, in these two weeks the endoderm transforms into differentiated organs as diverse as the lungs and the stomach. ... [Researchers] decided to create a knock-in reporter gene that would glow green during the 'fate decision' - the moment when the stem cells expressed a gene called Nkx2-1 and thereby took a step toward becoming lungs. This allowed the team to track the cells as they developed, mapping each of the six critical decisions on the path to lung tissue. ... Once [the] team had grown what appeared to be lung cells, they had to make sure they had the recipe right. They took samples of mouse lungs and rinsed them with detergent until they became cell-free lung-shaped scaffolds. They seeded one lung with 15-day-old homegrown lung cells that they had purified from stem cells. As a control, they seeded another lung with undifferentiated embryonic stem cells. Within 10 days after seeding, the lung cells organized themselves and populated the lung, creating a pattern recognizable [as] lung tissue. ... A happy side effect of the discovery was that the scientists also mapped out the road from stem cell to thyroid. [The] thyroid, it turns out, also comes from the endoderm layer, deriving from a progenitor that expresses the same key gene as lung progenitors. [The] work will likely have a huge impact on lung stem cell researchers, who have been waiting for a discovery like this to propel their research on inherited lung disease."

Link: http://www.bu.edu/today/2012/from-stem-cells-to-lung-cells/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Much like the practice of calorie restriction, exercise changes everything for the better in most people - it is far more effective in improving and sustaining long term health for the majority of us than any presently available medical technology. We need the future of better medicines that will achieve what good living cannot, such as rejuvenation of the elderly, absolute prevention of age-related disease, and radical life extension, but in the meanwhile it makes sense to make the most of present and proven methodologies to better out position as much as possible. People in the middle of life today will be cutting it fine under the most optimistic estimates for the development of working rejuvenation biotechnology - every year counts when it comes to either making future technology arrive more rapidly or being able to wait for longer.

The present phase of rapid development in biotechnology is uncovering a great deal of new knowledge when it comes to the workings of exercise: how exactly, down to the level of cells and signals, it improves health and life expectancy. For example, here is a paper on exercise and the brain:

The benefits of exercise and physical fitness on mental health and cognitive performance are well documented ... Animal studies have also demonstrated that exercise or physical activity produces very specific changes in the brain that are distinct from those produced by learning or novel experiences. ... Recently, studies have been carried out in humans using non-invasive brain imaging techniques to investigate exercise-related changes in brain structure. Such studies provide compelling evidence for the powerful effects of exercise on the brain, but also raise several questions. For example, do structural changes occur throughout the brain or are they limited to specific brain regions? What aspects of brain architecture are specifically modified by physical activity? On what time scale do these changes occur, and how persistent are they when exercise is discontinued? Do specific preconditions such as aging, disease, or genetic phenotypes make individuals more or less susceptible to activity-based brain changes?

...

Although relatively few studies exist on the effects of aerobic activity on the brain structure of healthy, younger individuals, there is a wealth of data demonstrating the cognitive benefits of frequent aerobic exercise throughout the lifespan - perhaps none more convincing than a recent study of 1.2 million Swedish military conscripts that showed a strong correlation between fitness and intelligence. Much work remains to be done to determine what level of aerobic activity is required for cognitive and brain health to be maximized, but it seems likely this level is well above that of the average individual.

You might compare that conclusion with data on life expectancy in athletes:

• Atheletes Live Longer, Probably the Exercise
• Putting Upper Bounds on Longevity Derived From Exercise

But equally, it seems clear that even moderate regular exercise has great benefits - the 80/20 point is probably somewhere in the vicinity of the venerable recommendation of 30 minutes of some aerobic activity. Sadly, even that level of exercise is probably "well above that of the average individual" in the wealthier nations.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Progress in the tissue engineering of cell structures for use as research tools, and later as the basis for therapies: "Three-dimensional clusters of pancreatic beta-cells that live much longer and secrete more insulin than single cells grown in the laboratory are valuable new tools for studying pancreatic diseases such as diabetes and for testing novel therapies. This cutting-edge advance is described in [an open access paper] ... Finding a solution for the culturing and final transplantation of pancreatic cells will be an enormous breakthrough for the treatment of diabetes ... Growing pancreatic cells in the laboratory is challenging, in part because to survive and function normally they require cell-cell contact. [Researchers] developed an innovative method that uses photolithography to create microwell cell culture environments that support the formation of 3-D pancreatic beta-cell clusters and control the size of the cell aggregates. They describe the ability to remove these cell clusters from the microwells and encapsulate them in hydrogels for subsequent testing or implantation."

Link: http://www.sciencecodex.com/new_method_yields_insulinproducing_pancreatic_cell_clusters-89204

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via ScienceDaily: "Individuals who suffer from autoimmune diseases also display a tendency to develop atherosclerosis - the condition popularly known as hardening of the arteries. Clinical researchers [have] now discovered a mechanism which helps to explain the connection between the two types of disorder. The link is provided by a specific class of immune cells called plasmacytoid dendritic cells (pDCs). ... Using laboratory mice as an experimental model, the researchers were able to show that pDCs contribute to early steps in the formation of athersclerotic lesions in the blood vessels. Stimulation of pDCs causes them to secrete large amounts of interferons, proteins that strongly stimulate inflammatory processes. The protein that induces the release of interferons is produced by immune cells that accumulate specifically at sites of inflammation, and mice that are unable to produce this protein also have fewer plaques. Stimulation of pDCs in turn leads to an increase in the numbers of macrophages present in plaques. Macrophages normally act as a clean-up crew, removing cell debris and fatty deposits by ingesting and degrading them. However, they can also 'overindulge,' taking up more fat than they can digest. When this happens, they turn into so-called foam cells that promote rather than combat atherosclerosis. In addition, activated, mature pDCs can initiate an immune response against certain molecules found in atherosclerotic lesions, which further exacerbates the whole process. ... The newly discovered involvement of pDCs in the development of atherosclerosis [reveals] why the stimulation of pDC that is characteristic of autoimmune diseases contributes to the progression of atherosclerosis. The findings also suggest new approaches to the treatment of chronic inflammation that could be useful for a whole range of diseases."

Link: http://www.sciencedaily.com/releases/2012/04/120404102943.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The SENS Foundation research community is steadily gathering momentum in their work on biotechnologies that, once fully realized, will be capable of rejuvenating the old - restoring youthful health, vigor, and function to the formerly declining organs and biological systems in the body. Even before then, the first applications resulting from SENS research will have a significant impact on health and age-related disease, achieved by partially reversing some of the root causes of aging. To go along with the recently released 2011 annual report, the SENS Foundation staff have also published their 2011 research report (in PDF format):

The subtitle on our logo banner reads "advancing rejuvenation biotechnologies", and in keeping with the dynamic connotations of that statement, we've spent 2011 engaged in focused, concrete actions toward embodying it. ... We're excited to be a part of this revolution in scientific innovation, grateful to everyone who has supported us through their generous gifts of time and funding, and delighted to have multiple exciting developments to report on the research front.

There is a lot of material in the report, and I encourage you to read the whole thing - it's very approachable for the layperson, and a good way to obtain a top to bottom view of the Foundation's research strategy at present. That more or less encompasses these questions: what exactly causes aging, and what can be done here and now to make progress towards preventing it and reversing it? For example, here's an excerpt from the GlycoSENS category, research with the potential to reverse the cause of much of the chemical and structural aging of skin, blood vessel walls, and many forms of connective tissue:

The elasticity of the artery wall, the flexibility of the lens of the eye, and the high tensile strength of the ligaments are examples of tissues that rely on maintaining their proper structure. But chemical reactions with other molecules in the extracellular space occasionally result in a chemical bond (a so-called crosslink) between two nearby proteins that were previously free-moving, impairing their ability to slide across or along each other and thereby impairing function. It is the goal of this project to identify chemicals that can react with these crosslinks and break them without reacting with anything that we don't want to break.

...

In 2011, we established a Center of Excellence for GlycoSENS and other rejuvenation research at Cambridge University and hired postdoctoral student Rhian Grainger to design and perform experiments to develop reagents that can detect proteins bearing glucosepane crosslinks, facilitating further studies on its structure, abundance, and cleavage by small molecules. We also established a collaboration with researchers at Yale University, who will lend their expertise in generating advanced glycation end-products and lead efforts in developing agents which may be able to cleave glucosepane.

There are other projects recently started by the Foundation in other areas of the SENS program. You'll also find progress reports for the work that has been ongoing for some years: the MitoSENS project to block the contribution of mitochondrial DNA damage to aging, and the LysoSENS biomedical remediation work that is a search for enzymes to safely remove the build up of damaging compounds that the body's recycling mechanisms cannot cope with on their own.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An introduction to calorie restriction at h+ Magazine: "In the early twentieth century nutrition researchers found that rats maintained on reduced caloric intake showed lower spontaneous tumors compared to rats fed ad libitum (allowed to eat as much as they chose). Although this work did not address caloric restriction (CR) and aging, it suggested that CR might slow the onset of age-associated disease in rodents. ... Numerous follow-up studies demonstrated that a micronutrient adequate CR diet significantly increased the lifespan of many species, largely crossing species boundaries. ... While CR increases the lifespans of most species examined, it also suppresses many of the diseases associated with human aging, thus increasing the 'health-span.' Over short periods, CR lowers blood pressure, heart rate, and glucose levels, and improves memory in older individuals and measures of cognitive performance in animals. Over longer periods CR significantly reduces the risk for many different types of cancer, age-related brain atrophy, heart disease (and atherosclerosis related diseases), autoimmune disease, and adult onset diabetes. CR appears to lessen the risk for, and attenuates or even reverses the symptoms of Alzheimer's and possibly Parkinson's diseases; two major age-related neurodegenerative diseases that cause enormous human suffering. ... Interestingly, CR appears to promote the progression of Amyotrophic Lateral Sclerosis (Lou Gehrig's disease), indicating it does not protect from all human diseases. Aging causes extensive, often organ-specific changes in gene expression patterns. Analysis [has] shown that aging, calorically restricted mice show gene expression patterns resembling those of young animals, compared to ad libitum-fed mice of the same age. CR also lowers cellular oxidative damage by reducing mitochondrial oxygen free radical production, lessens age-related telomere shortening, lowers inflammation, increases DNA damage repair efficiency and lowers damage to DNA and RNA (thus promoting genomic stability), lowers insulin levels while promoting insulin sensitivity, reduces the number of senescent (non-dividing) cells that accumulate with aging, attenuates age-related cellular protein cross-linking, and increases the removal of damaged cellular proteins - a process called 'autophagy' which declines with age and plays a role in resistance to infection, cancer, heart disease, and neurodegeneration. "

Link: http://hplusmagazine.com/2012/04/04/caloric-restriction-and-longevity/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

An open access review paper: "Several studies suggest that an increase in adult neurogenesis has beneficial effects on emotional behavior and cognitive performance including learning and memory. The observation that aging has a negative effect on the proliferation of neural stem cells has prompted several laboratories to investigate new systems to artificially increase neurogenesis in senescent animals as a means to compensate for age-related cognitive decline. ... recent evidences indicate that the relative abundance of stem cells in certain organs does not necessarily correlate with their impact on organ function. Specifically, the mammalian brain is perhaps the organ with the lowest regenerative potential but the one in which the signs of aging are more manifested. Using the words of the renaissance writer Michel de Montaigne, 'age imprints more wrinkles on the mind than it does on the face' indicating that age-related cognitive decline has the highest impact on the quality of life. To which extent this decline is dependent on neural stem and progenitor cells (together referred to as NSCs) is hard to tell but growing evidences indicate that, despite their negligible numbers, the few resident NSCs that are located in specific brain regions, most notably the subgranular zone of the hippocampus, seem to play a major role in cognitive functions such as learning, memory, and emotional behavior by generating, through intermediate progenitors, neurons that are constantly added to the brain circuitry throughout life. ... the available data strongly suggests that aging almost exclusively acts at the level of NSC proliferation. Yet, the many contradicting results and uncertainties on identifying the exact causes of this 'decreased proliferation' [need] to be fully acknowledged in order to give a rigorous and meaningful direction to this relatively new field. ... The fact that NSCs can efficiently respond to physiological and pathological stimuli to increase neurogenesis indicates that stimulation of endogenous NSCs offers a promising alternative to transplantation approaches that until now were intensely investigated."

Link: http://impactaging.com/papers/v4/n3/full/100446.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Kingsley G. Morse Jr. is one of the regulars at the Gerontology Research Group mailing list. He maintains a spreadsheet of all the life span studies in various organisms that he has been able to find, and is generally willing to sell that data at white paper rates, should you happen to be interested. He recently posted a histogram assembled from the study results, which I'm sure you'll agree is interesting:

The history of working to extend life in laboratory animals - and of studying effects on longevity and mortality in humans - is largely a big null result. Other than calorie restriction, the effects of which were first formally cataloged by scientists in the 1930s, all of the excitement shows up in the past twenty years or so. The successes are a tiny fraction of the studies that showed nothing, or showed a result well within the margin of error, or produced results that could not be replicated. In mammals, mostly mice, the bulk of studies that do extend life significantly fall in to the 15% to 30% life extension bracket - on a par with moderate to severe calorie restriction. Only a few methods have been demonstrated to reach beyond that point.

To a large degree this is because near everything tried to date has been a form of metabolic manipulation - change the operation of metabolism to slow the effective rate at which damage accrues to the organism. I would be surprised to see any great improvement in the length of life lived by laboratory animals until the research community changes strategy to focus on actually repairing and reversing the cellular and molecular damage that causes aging. The difference between slowing aging and repairing aging will be as night and day when it comes to the practical results that can be achieved.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm